Transcriptional Regulation of the Interferon- γ-inducible Tryptophanyl-tRNA Synthetase Includes Alternative Splicing (∗)

We have investigated the transcriptional control elements of the human interferon (IFN)- γ-induced tryptophanyl-tRNA synthetase ( hWRS ) gene and characterized the transcripts. Transcription leads to a series of mRNAs with different combinations of the first exons. The full-length mRNA codes for a 55-kDa protein (hWRS), but a mRNA lacking exon II is present in almost as high amounts as the full-length transcript. This alternatively spliced mRNA is probably translated into a 48-kDa protein starting from Met 48 in exon III. The predicted 48-kDa protein corresponds exactly to an IFN- γ-inducible protein previously detected by two-dimensional gel electrophoresis. By isolation of genomic clones and construction of plasmids containing hWRS promoter fragments fused to the secreted alkaline phosphatase reporter gene we have mapped a promoter region essential for IFN-mediated gene activation. This region contains IFN-stimulated response elements (ISRE) as well as a Y-box and a γ-activated sequence (GAS) element. IFN- γ inducibility of hWRS depends on ongoing protein synthesis, suggesting that so far undescribed transcription factors apart from the latent GAS-binding protein p91 contribute to gene activation. This could be interferon-regulatory factor-1, which binds ISRE elements.